1. Field of the Invention
This invention relates to substituted alkenyltetrazole derivatives which are used in the field of the medicine for improving by decreasing the symptoms caused by thromboxane. Concretely speaking, this invention relates to substituted bicycloheptylalkenyltetrazole derivatives or a pharmaceutically acceptable salt thereof which are useful as antithrombotic, antivasoconstricting, and anti-bronchoconstricting drugs.
2. Description of the Prior Art
The general course of atherosclerosis, which is regarded as the main risk factor of myocardial infarction and cerebral infarct, begins in the arterial intima with mucoid accumulation and fibroblast formation, progressively followed by degeneration, lipid and cholesterol deposition, and destruction and atheromasia of the intima tissue, with gradual formation of high-degree and localized hypertrophy in the intima. The atherosclerosis has long been regarded to be caused by thrombus formation and fibrin deposition, but recent discoveries of thromboxane A.sub.2 (TXA.sub.2) by Samuelsson et al. and prostacyclin (PGI.sub.2) by Vane et al. have revealed an interaction between platelets and vessel wall. Platelets are said to play an important role in the onset and progress of atherosclerosis. Therefore, it is now recognized that the use of antithrombotic drugs, particularly drugs which inhibits platelet aggregation, are effective for the treatment of atherosclerotic diseases.
In addition to the conventional antithrombotic drugs such as heparin and coumarin compounds, certain types of prostaglandins are known to have a potent platelet aggregation inhibitory action. From these facts, prostaglandin derivatives have attracted much attention as possible antithrombotic drugs. For example, analogues of Prostaglandin E.sub.1 and I.sub.2 receptor agonists have been developed. Since thromboxane A.sub.2 shows potent platelet aggregation and vasoconstriction action, thromboxane A.sub.2 synthesis inhibitors, such as cyclooxygenase inhibitors and thromboxane synthetase inhibitors, and thromboxane A.sub.2 receptor antagonists, have been developed. The thromboxane A.sub.2 receptor antagonists include 13-APA [Venton D.L. et al., J. Med. Chem., 22, 824 (1979)], PTA.sub.2 [Lefer A.M. et al., Proc. Natl. Acad. Sci. U.S.A., 76, 2566, (1979)], BM-13177 [Lefer A.M. et al., Drugs of Today, 21, 283 (1985)], SQ-29548 [Ogletree et al., J. Pharmacol. Exp. Ther., 34, 435 (1985)], and the like. Japan Kokai Patent Publication No. 88-139161 and U.S. Patent No. 4654375 also include the compound of this type. The tetrazole derivatives of physiologically active carboxylic acids of these kind are disclosed in J. Med. Chem., 22, 1340, (1979) or the like.
When thrombin acts on platelets, cyclooxygenase is activated. By activation of cyclooxygenease, thromboxane A.sub.2 is produced enzymatically in platelets, vessel wall, and various other cells, from arachidonic acid through prostaglandins G.sub.2 and H.sub.2. This product has various potent physiologic or pathogenic actions. In particular, the potent platelet aggregation action and the action constricting the smooth muscle of bronchi and of coronary, cerebral, and pulmonary arteries, etc. are considered to be the factors which relate to the onset and progress of such circulatory and respiratory diseases as angina pectoris, myocardial infarction, cerebral infarction, and bronchial asthma. Moreover, it is said that the strong action occurs even at a concentration of 10.sup.-10 -10.sup.-11 M. Therefore, increasing attention has been paid to the development of thromboxane A.sub.2 antagonists or inhibitors as anti-thrombotics, anti-vasoconstrictives or anti-bronchoconstrictives. Inhibitors, however, have some problems in view of the fact that they influence on prostaglandins which bear various important roles as well as thromboxane A.sub.2, and uncontrolled thromboxane-like harmful effects are caused by accumulated substrates. So, development of receptor antagonists has especially been sought. However, this kind of antagonist has some problems, e.g., short action, emergence of partial agonistic action, hardness to separate traget effect from potential effects, or the like.